NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

高三角洲和高Mu亲和力的性质研究 分别测定了肾上腺素和地吗啡的选择性。 用近150个合成类似物分析阿片类药物的相互作用 通过大脑感受器。我们与Deltorphins A、B和C的数据强调了 以下是关于增量亲和力要求的结论 选择性：(1)选择性反转发生在阶跃N- C-末端天冬氨酸残基的末端移动；(2) 6位氨基酸残基的侧链与此关系不大 受体相互作用；(3)残基4或7上的大体积保护基团，或 两者都减少了与Delta受体的结合；(4)对卤化 苯丙氨酸的苯环增强脑三角洲受体结合和 然而，通过使用药理学范式测量的生物活性，但是 两种化验的卤素不同，这进一步证明了 中枢和外周阿片受体的差异；另一方面 手性、氨基或硝基衍生物不利于结合和 受体Mu亲和力与亲脂性和GPI的异常相关性 生物活性；(5)苯丙氨酸的取代表明 受体可修饰为芳香族苯环所在的配体 垂直于但不在肽骨架平面内；(6) 从N-末端延伸的分子或在残基1，4之间桥联的分子 表现出更低的选择性，但提供了证据表明三角洲 受体可以容纳显着修饰的酪氨酸残基。数据 德吗啡为生产超级激动剂开辟了新的前景 具有增强的MU结合活性。初步的计算机模拟 Deltorphins倾向于证实核磁共振分析 这些多肽在溶液中表现出一定程度的结构完整性；即， N-末端区域形成II型β-转角，其中D-丙氨酸和 苯丙氨酸是形成折叠结构的关键残基 通过内部氢键发生，以帮助其稳定 灵活的天性。神经母细胞瘤细胞阿片受体的下调 培养表明G蛋白和未知因素是相关因素 可能与药物成瘾有关的调节反应。

Investigations on the properties of the high delta and mu affinities and selectivities of deltorphins and dermorphin, respectively, was undertaken with nearly 150 synthetic analogues to analyze the interaction of opioids with brain receptors. Our data with deltorphins A, B, and C underscored the following conclusions concerning the requirement for delta affinity and selectivity: (1) reversal of selectivity occurred upon the stepwise N- terminal shift of the C-terminal Asp residue; (2) the lipophilicity of the side-chain of the amino acid residue at position 6 had little bearing on receptor interaction; (3) bulky protective groups on residues 4 or 7, or both, diminished binding to delta receptors; (4) para halogenation of the benzyl ring of phenylalanine enhanced both brain delta receptor binding and bioactivity as measured by use of pharmacological paradigms, however, but not the same halogen for both assays, which further serves to demonstrate differences between central and peripheral opioid receptors; on the other hand, amino or nitro derivatives were detrimental for binding and an anomalous correlation of receptor mu affinity to the lipophilicity and GPI bioactivity; (5) substitutions of phenylalanine suggested that the delta receptor is amendable to ligands in which the aromatic benzyl ring lies perpendicular to, but not in, the plane of the peptide backbone; (6) molecules extended from the N-terminus or bridged between residue 1 4 exhibited reduced selectivity, yet provided evidence that the delta receptor can accommodate a significantly modified tyrosine residue. Data with dermorphins opened new vistas for the production of super agonists with enhanced mu binding activity. Preliminary computer modeling of the deltorphins tends to confirm the nuclear magnetic resonance analyses that these peptides exhibit a degree of structural integrity in solution; i.e., the N-terminal region forms and type II beta-turn, in which D-alanine and phenylalanine are critical residues and the formation of a folded structure occurs through internal hydrogen bonds to assist in stabilization of its flexible nature. Down regulation of opioid receptors in neuroblastoma cell cultures suggested that G-proteins and unidentified factors are responsible for the modulatory response that may be involved in drug addiction.